Coming off a victory Sunday in the Hall of Fame Open in Newport, Rhode Island, Isner is seeking his fourth Atlanta title in five seasons. He lost to Nick Kyrgios in the final last year.
Isner set up a quarterfinal match at Atlantic Station against Slovakia's Lukas Lacko, a 6-3, 6-1 winner over sixth-seeded Donald Young. The American has 11 career titles, all at the ATP World Tour 250 level.
Third-seeded Gilles Muller of Luxembourg and Tommy Paul also reached the quarterfinals. Muller beat France's Quentin Halys 6-4, 6-7 (1), 6-3, and Paul topped Tunisia's Malek Jaziri 6-7 (5), 6-4, 6-3.
In the top half of the draw, top-seeded Jack Sock will open play Thursday with a second-round match against Israel's Dudi Sela.